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| United States Patent |
6,057,474
|
|
Vallejos
, et al.
|
May 2, 2000
|
Preparation process for .alpha., .beta.-dicarbonylated compounds
Abstract
Preparation process for .alpha.,.beta.-dicarbonylated compounds of formula
(I)
##STR1##
in which R.sub.2 =alkyl, phenyl or benzyl being able to be substituted in
various ways on the cycle, or carboxylic ester, and R.sub.3 =alkyl or
alkoxy or carboxylic ester in which a compound of formula (II)
##STR2##
in which R.sub.1 =alkyl, or alkyl .alpha.-ketocarboxylate or carboxylic
ester, and R.sub.2 and R.sub.3 have the same meanings as previously is
reacted in a nitrile type solvent, with molecular oxygen in the presence
of copper.sup.II nitrate or ferric chloride as catalyst, and use for
obtaining ethyl .alpha.-ketobutyrate, ethyl phenyl pyruvate, ethyl
pyruvate, ethyl phenylglyoxylate, butane-2,3-dione or diethyl mesoxalate.
| Inventors:
|
Vallejos; Jean-Claude (Marseilles, FR);
Capelle; Nicolas (Nimes, FR);
Arzoumanian; Henri (Aubagne, FR)
|
| Assignee:
|
Clariant S.A. (Puteaux, FR)
|
| Appl. No.:
|
217616 |
| Filed:
|
December 22, 1998 |
Foreign Application Priority Data
| Current U.S. Class: |
560/51; 560/174; 568/312; 568/389 |
| Intern'l Class: |
C07C 069/76; C07C 069/72; C07C 045/32; C07C 045/33 |
| Field of Search: |
560/51,54,174
568/312,389
|
References Cited
U.S. Patent Documents
| 5523459 | Jun., 1996 | Hirai et al. | 560/51.
|
Other References
J. Cossy et al., "Oxidative cleavage of 2-substituted cycloalkane-1,
3-diones and of cyclic beta-ketoesters by copper perchlorate/oxygen.",
Tetrahedron Letters, vol. 35, No. 22, Aug. 15, 1994, pp. 6089-6092.
Ahmed Atlamsani et al., "Synthesis of 5-and 6-oxoalkanoic acids by
copper(II)-catalized oxidative cleavage of cycloalkanones with dioxygen.",
Synthesis, No. 1, Jan. 1993, pp. 79-81.
Zong-Xing Si et al., "A facile general route to alpha-keto esters and
alpha-diketones.", Synthesis, No. 6, Jun. 1990, pp. 509-510.
Ito S. et al., "Ferric salt catalyzed oxydation of cycloalkanones to oxo
esters by molecular oxygen.", Journal of Organic Chemistry, vol. 48, No.
7, Apr. 8, 1983, pp. 1133-1135.
|
Primary Examiner: Keys; Rosalynd
Attorney, Agent or Firm: Browdy and Neimark
Claims
We claim:
1. Preparation process for .alpha.,.beta.-dicarbonylated compounds of
formula (I)
##STR9##
in which R.sub.2 represents an alkyl radical containing 1 to 6 carbon
atoms, or a phenyl radical or a benzyl radical being able to be
substituted in various ways on the cycle, or a carboxylic ester radical
containing 2 to 5 carbon atoms, and R.sub.3 represents an alkyl radical
containing 1 to 4 carbon atoms, or an alkoxy radical containing 1 to 4
carbon atoms, or a carboxylic ester radical containing 2 to 5 carbon atoms
characterized in that an .alpha.,.gamma. dicarbonylated compound of
formula (II)
##STR10##
in which R.sub.1 represents an alkyl radical containing 1 to 6 carbon
atoms, or an alkyl .alpha.-ketocarboxylate radical containing 3 to 6
carbon atoms or a carboxylic ester radical containing 2 to 5 carbon atoms,
and R.sub.2 and R.sub.3 have the same meanings as previously is reacted in
a nitrile solvent, with molecular oxygen in the presence of copper.sup.II
nitrate or ferric chloride as catalyst.
2. Process according to claim 1, characterized in that the reaction solvent
is an aliphatic or aromatic nitrile solvent.
3. Process according to claim 2, characterized in that the reaction solvent
is of an aliphatic nitrile.
4. Process according to claim 3, characterized in that the quantity of
copper.sup.II nitrate or ferric chloride is comprised between 0.1 molar
equivalent and 0.001 molar equivalent with respect to the starting
substrate of formula (II).
5. Process according to claim 4, characterized in that the quantity of
copper.sup.II nitrate or ferric chloride is comprised between 0.05 molar
equivalent and 0.01 molar equivalent with respect to the starting
substrate of general formula (II).
6. Process according to claim 5, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved by bubbling oxygen or
air through the reaction mixture.
7. Process according to claim 5, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved under an oxygen
pressure of 1 to 5 atmospheres.
8. Process according to claim 7, characterized in that the oxygen used
comes from an air supply or under an air pressure.
9. Process according to claim 6, characterized in that the oxygen used
comes from an air supply or under an air pressure.
10. Process according to claim 1, characterized in that the quantity of
copper.sup.II nitrate or ferric chloride is comprised between 0.1 molar
equivalent and 0.001 molar equivalent with respect to the starting
substrate of formula (II).
11. Process according to claim 10, characterized in that the quantity of
copper.sup.II nitrate or ferric chloride is comprised between 0.05 molar
equivalent and 0.01 molar equivalent with respect to the starting
substrate of general formula (II).
12. Process according to claim 1, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved by bubbling oxygen or
air through the reaction mixture.
13. Process according to claim 1, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved under an oxygen
pressure of 1 to 5 atmospheres.
14. Process according to claim 3, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved by bubbling oxygen or
air through the reaction mixture.
15. Process according to claim 3, characterized in that the reaction is
carried out in a medium saturated in oxygen achieved under an oxygen
pressure of 1 to 5 atmospheres.
16. In a method of making a compound of ethyl .alpha.-ketobutyrate, ethyl
phenylpyruvate, ethyl pyruvate, ethyl phenylglyoxylate, butane-2, 3-dione
or diethyl mesoxalate comprising carrying out the process of claim 1 and
recovering said compound.
17. In a method of making a compound of ethyl .alpha.-ketobutyrate, ethyl
phenylpyruvate, ethyl pyruvate, ethyl phenylglyoxylate, butane-2, 3-dione
or diethyl mesoxalate comprising carrying out the process of claim 2 and
recovering said compound.
18. In a method of making a compound of ethyl .alpha.-ketobutyrate, ethyl
phenylpyruvate, ethyl pyruvate, ethyl phenylglyoxylate, butane-2, 3-dione
or diethyl mesoxalate comprising carrying out the process of claim 3 and
recovering said compound.
19. In a method of making a compound of ethyl .alpha.-ketobutyrate, ethyl
phenylpyruvate, ethyl pyruvate, ethyl phenylglyoxylate, butane-2, 3-dione
or diethyl mesoxalate comprising carrying out the process of claim 4 and
recovering said compound.
Description
The present invention relates to a preparation process for
.alpha.,.beta.-dicarbonylated compounds.
In the literature, there are numerous synthetic routes for .alpha.-keto
esters, .alpha.-keto acids and .alpha.,.beta.-diketones.
For example, the following can be mentioned:
Kovacs, L. Recd. Trav. Chim. Netherlands 112, 471-496 (1996)
Cooper, A. J. L. et al, Chem.Rev. 83, 321-358 (1983),
Weinstock, L. M. et al, Synth. Comm. 11, 943 (1981),
Wislicenus Ber20., 592 (1887),
Friedman, L. and Kosower E. Organic Syntheses, Coll. Vol. III, 510,
Sohda, T. et al, Chem. Pharm. Bull. 30, 3601 (1982),
Inokushi, T. et al, Chem. Lett. 8, 1411-1414 (1994),
Muckawa, H. et al., Chem. Lett. 6, 1017-1020 (1994),
Bouveault, L. and Locquin R. Bull. Soc. Chim. Fr, 31, 1049, 1055, 1061,
1143(1904)
Locquin, R. Bull Soc. Chim. Fr. 31, 1068, 1147 (1904),
Si, Z et al, Synthesis 6, 509-510 (1990).
But none of the syntheses described allows an industrial use to be
envisaged.
In fact, the processes described require either raw materials that are
rarely available on the market, or expensive reagents, or operating
conditions that cannot be recreated in an industrial environment, or are
processes causing pollution.
Now, the Applicant was surprised to discover that it was possible to obtain
.alpha.,.beta.-dicarbonylated compounds economically and with good yields
by reacting an appropriate starting compound with molecular oxygen in the
presence of small quantities of an appropriate catalyst in an appropriate
reaction solvent.
For this reason, a subject of the present Application is a preparation
process for .alpha.,.beta.-dicarbonylated compounds of formula (I)
##STR3##
in which R.sub.2 represents an alkyl radical containing 1 to 6 carbon
atoms, or a phenyl radical or a benzyl radical, being able to be
substituted in various ways on the cycle, in particular by alkyl
substituents containing 1 to 6 carbon atoms, by alkoxy substituents
containing 1 to 4 carbon atoms or by halogen substituents or a carboxylic
ester radical containing 2 to 5 carbon atoms and R.sub.3 represents an
alkyl radical containing 1 to 4 carbon atoms, or an alkoxy radical
containing 1 to 4 carbon atoms or a carboxylic ester radical containing 2
to 5 carbon atoms, characterized in that an .alpha.,.gamma. dicarbonylated
compound of formula (II)
##STR4##
in which R.sub.1 represents an alkyl radical containing 1 to 6 carbon
atoms, or an alkyl .alpha.-keto carboxylate radical containing 3 to 6
carbon atoms or a carboxylic ester radical containing 2 to 5 carbon atoms
and R.sub.2 and R.sub.3 have the same meanings as previously, is reacted
in a nitrile type solvent with molecular oxygen in the presence of
copper.sup.II nitrate or ferric chloride as catalyst.
The .alpha.,.beta.-dicarbonylated compounds of formula I relate essentially
to .alpha.-keto esters that provide access to .alpha.-keto acids and their
derivatives which are very useful molecules both for use in biological
systems and in organic synthesis. In fact, certain .alpha.-keto acids are
used in the treatment of patients undergoing dialysis, this is the case,
for example, for methylethyl pyruvic acid, dimethyl pyruvic acid or
isopropyl pyruvic acid. Moreover, they are of great use as intermediates
for numerous syntheses such as those for medicaments, inhibition enzymes,
.alpha.-hydroxy acids, c-nucleosides, natural products, as well as for the
synthesis of a large number of heterocycles.
They can also be .alpha.,.beta.-diketones, very useful compounds for use in
organic synthesis.
As an appropriate catalyst, it was discovered, surprisingly, that among the
numerous salts of copper, iron, cobalt and manganese tested, only
copper.sup.II nitrate and ferric chloride give useful synthesis yields
which can be used industrially.
In addition, as an appropriate reaction solvent, it was discovered,
surprisingly, that among the catalysts selected, only solvents of nitrile
type, in particular aliphatic or aromatic, allowed synthesis yields to be
obtained that are useful and can be used industrially, solvents of the
aliphatic type giving the best yields.
The process according to the present invention allows
.alpha.,.beta.-dicarbonylated compounds of formula (I) above to be
obtained economically and with good yields.
In formula I, in formula II and hereafter, the term alkyl radical
containing 1 to 6 carbon atoms represents, for example, a methyl, ethyl,
propyl, butyl, hexyl, cyclohexyl radical, preferably a methyl or ethyl
radical, and in particular an ethyl radical.
In formula I and hereafter, the phenyl radical and benzyl radical can be
substituted in various ways on the cycle by one or more substituents,
preferably by 3 or 2 or 1 alkyl substituents containing 1 to 6 carbon
atoms, alkoxy containing 1 to 4 carbon or halogen atoms, preferably
chlorine or bromine and is preferably not substituted.
In formula I and hereafter, the term alkoxy radical containing 1 to 4
carbon atoms represents, for example, a butoxy or propyloxy or ethoxy or
methoxy radical, preferably an ethoxy or methoxy radical and in particular
an ethoxy radical.
In formula I, in formula II and hereafter, the term carboxylic ester
radical containing 2 to 5 carbon atoms represents, for example, a butyl or
propyl or ethyl or methyl carboxylate, preferably an ethyl or methyl
carboxylate radical and in particular an ethyl carboxylate.
In formula II and hereafter, the term alkyl .alpha.-ketocarboxylate radical
containing 3 to 6 carbon atoms represents, for example, a butyl, propyl,
ethyl or methyl .alpha.-ketocarboxylate radical, preferably an ethyl or
methyl .alpha.-keto carboxylate radical and in particular an ethyl
.alpha.-ketocarboxylate radical.
Under preferred conditions for implementing the process of the invention,
the nitrile-type reaction solvent will be of an aliphatic nitrile type,
most particularly acetonitrile.
According to other preferred conditions for implementing the above process,
the quantity of copper.sup.II nitrate or ferric chloride will be comprised
between 0.1 molar equivalent and 0.001 molar equivalent and more
particularly between 0.05 and 0.01 molar equivalent with respect to the
starting substrate of formula (II).
According to other preferred conditions for implementing the above process,
the reaction will be carried out in a medium saturated in oxygen, achieved
by bubbling oxygen or air through the reaction medium.
According to other preferred conditions for implementing the above process,
the reaction will be carried out in a medium saturated in oxygen, achieved
under an oxygen pressure of 1 to 5 atmospheres.
Again under preferred conditions for implementing the above process, the
oxygen used comes from an air supply or under an air pressure.
The process according to the invention will more particularly be
implemented at ambient temperature but can be carried out at a higher
temperature in order to reduce the reaction time or the quantity of
catalyst used.
It should be further specified that the process according to the invention
is enhanced by a greater dilution of the substrate in the nitrile-type
solvent but that for an industrial use of the process, it is preferable to
work at a concentration of the order of 20 to 25% by weight of the
substrate in the nitrile-type solvent.
The process according to the invention is advantageously implemented by
mixing in a receptacle such as a three-necked flask, 1 molar equivalent of
the substrate of formula II, 0.05 to 0.01 molar equivalent of
copper.sup.II nitrate or ferric chloride and 75 to 80% by weight of the
nitrile-type solvent with respect to the weight of the substrate.
Preferably, the mixture is agitated whilst being maintained at the desired
temperature, most often at ambient temperature, in particular while
saturating the reaction atmosphere in oxygen by bubbling through or under
a pressure of to 1 to 5 atmospheres.
The .alpha.,.beta.-dicarbonylated compound formed is then determined in the
reaction medium. This product can be isolated and purified by methods
known per se, and explained in the examples illustrating the present
invention.
Among the .alpha.,.beta.-dicarbonylated compounds of formula I accessible
by the process of the present invention, there can be mentioned:
ethyl .alpha.-ketohexanoate
ethyl .alpha.-ketobutyrate
ethyl phenylpyruvate
ethyl pyruvate
ethyl phenylglyoxylate
butane-2,3-dione
diethyl mesoxalate
A subject of the present Application is also the use of the above process
to obtain the above-mentioned .alpha.,.beta.-dicarbonylated compounds of
formula (I) and in particular those above.
The following examples allow the present invention to be better understood.
EXAMPLE 1
In a 125 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a tube supplying oxygen and a condenser surmounted by a gas
washing bottle, the following are introduced:
24.7 g (0.13 mol., 1 eq.) of ethyl 2-n butylacetoacetate (purity 97%)
0.3204 g (1.3 mmoles, 0.01 eq.) of trihydrated copper.sup.II nitrate
(purity 99% min)
and 100 g of acetonitrile.
The mixture is agitated under oxygen bubbling (100 ml/mn) whilst
maintaining the temperature at 20-25.degree. C. with a water bath.
The solvent and acetic acid formed are evaporated off under reduced
pressure. Then, 100 ml of ethyl acetate and 30 ml of water are added.
Agitation is carried out and the phases are separated. The organic phase
is washed with 10 ml of water. Then the ethyl acetate is evaporated off
under reduced pressure. The 23 g of crude product obtained are distilled.
17 g of ethyl .alpha.-ketohexanoate (83% yield) is recovered which
distills at 68.degree. C./4 mmHg (lit. 84.degree. C./10 mmHg).
(The structure of the product was confirmed by H.sup.1 NMR analysis 200
MHz).
EXAMPLE 2
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube supplying oxygen and a condenser surmounted by a
gas washing bottle, the following are introduced:
0.98 g (6 mmoles) of ethyl 2-ethyl acetoacetate (purity .about.97%),
0.0476 g (0.3 mmole, 0.05 eq.) of ferric chloride (purity .about.98%), and
23.5 g of acetonitrile.
The mixture is agitated at 20.degree. C. under oxygen bubbling (.about.30
ml/mn).
After reaction for 6 hours, 0.78 g of ethyl .alpha.-ketobutyrate, i.e. a
yield of 80% is determined in the medium by HPLC (by external calibration,
after oximation with methoxylamine).
EXAMPLE 3
In a 500 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube, a condenser surmounted by a gas washing bottle,
the following are introduced:
33 g of ethyl 2-benzylacetoacetate (purity 98% min) (0.147 moles),
1.80 g of trihydrated copper nitrate (purity 99% min) (7.45 mmoles), and
300 g of acetonitrile.
The reaction mixture is maintained for 6 hours at 20.degree. C. under
agitation and oxygen is bubbled through (60 ml/mn).
10 g of IRC 718 resin (Rohm and Haas) is added. The reaction mixture is
maintained under agitation for 1 hour at ambient temperature, then the
resin is filtered and washed on the filter with a little acetonitrile. The
medium is concentrated at 40.degree. C. with a rotary evaporator under
reduced pressure provided by the water pump, then the crude product
obtained is distilled. 2.5 g of benzaldehyde (boiling point=55.degree. C.
under 2 mm of Hg) is recovered, then 7.5 g of a yellow oil which distills
at 110-115.degree. C. under 1 mm of Hg is recovered (lit. 149-151.degree.
C. under 15 mm of Hg) which is identified by NMR as being ethyl
phenylpyruvate containing a small quantity of the enol form, structure
confirmed by H.sup.1 NMR200 Mz. The yield of ethyl phenylpyruvate is 27%
with respect to the starting product.
EXAMPLE 4
In a 100 ml three-necked flask equipped with a thermometer, mechanical
agitation, a condenser surmounted by a gas washing bottle, the following
is introduced:
2.80 g of diethyl methylmalonate (purity 99%) (16 mmoles),
0.194 mg of trihydrated coppe/l nitrate (purity 99% min.) (0.8 mmole), and
32.2 g of acetonitrile.
The reaction mixture is maintained under agitation for 16 hours and oxygen
is bubbled through (30 ml/mn). 1.74 g of ethyl pyruvate, i.e. a yield of
93.5% is determined by HPLC (by external calibration after oximation with
methoxylamine).
EXAMPLE 5
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube supplying oxygen and a condenser surmounted by a
gas washing bottle, the following are introduced:
2.8 g (13 mmoles) of crude diethyl-2oxalylbutyrate (synthesized according
to Organic Synthesis Coll. Vol. II, 272-273),
0.151 g (0.65 mmole) of trihydrated copper II nitrate (purity 99% min.),
and
32.2 g of acetonitrile.
The reaction mixture is maintained under agitation and oxygen is bubbled
for 16 hours at T=20.degree. C. 1.44 g of ethyl .alpha.-ketobutyrate, i.e.
a yield of 84.5% is determined in the reaction medium by HPLC (by external
calibration after oximation with methoxylamine).
EXAMPLE 6
In a 500 ml three-necked flask equipped with a thermometer, mechanical
agitation and a dipping tube for supplying oxygen, the following are
introduced:
50 g of diethyl phenyl malonate (purity 98%) (0.207 mole),
2.55 g of copper.sup.II nitrate (purity 99% min) (10.5 mmoles), and
450 g of acetonitrile.
The reaction mixture is maintained under agitation and oxygen is bubbled
through (60 ml/mn) for 12 hours at a temperature of 20.degree. C. 20 g of
the IRC 718 resin (Rohm and Haas) is added to the reaction medium and
agitation is maintained for 1 hour at ambient temperature. The resin is
filtered and washed with a small amount of acetonitrile. The filtrate is
concentrated with a rotary evaporator under reduced pressure with a water
pump, then distilled. The fraction which distills at 95-100.degree. C.
under 1 mm of Hg (lit. 80.degree. C. under 0.2 mmHg) is recovered, i.e.
27.5 g corresponding to a yield of 74.6%.
The ethyl phenylglyoxylate structure was confirmed by H.sup.1 NMR analysis
200 Mz.
EXAMPLE 7
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a gas supply and a condenser surmounted by a gas washing bottle,
the following are introduced:
1.1571 g (9.7 mmoles) of 3-methylacetylacetone (technical)
0.1188 g (0.48 mmole) of trihydrated copper.sup.II nitrate (purity 99%
min.), and
23.5 g of acetonitrile.
The temperature of the mixture is reduced to 5-10.degree. C. with an ice
bath. The reaction mixture is agitated under oxygen bubbling (30 ml/mn).
0.57 g of butan-2,3-dione (68% yield) is determined in the reaction medium
by HPLC (by external calibration after oximation with methoxylamine) after
8 hours.
EXAMPLE 8
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube supplying oxygen and a condenser surmounted by a
gas washing bottle, the following are introduced:
0.656 g of diethyl 2-acetylmalonate techn. (3.24 mmoles),
0.0466 g of tridhydrated copper.sup.II nitrate (purity 99% min) (0.188
mmole), and
17 g of acetonitrile.
The reaction mixture is maintained under agitation and oxygen is bubbled
through it (.about.30 ml/mn) at 20.degree. C. for 16 hours. 1 g of IRC 718
resin (Rohm and Haas) is added. The reaction mixture is maintained under
agitation for 1 hour at ambient temperature. The resin is filtered and
washed with a small amount of acetonitrile. In the filtrate (18.7 g), 0.20
g of diethyl mesoxalate, i.e. a yield of 32.5% is determined by capilliary
GC (internal calibration, diethyl oxalate standard).
COMPARISON EXAMPLE 1
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube supplying oxygen and a condenser surmounted by a
gas washing bottle, the following are introduced:
0.98 g (6 mmoles) of ethyl 2-ethylacetoacetate (purity .about.97%),
catalyst at the rate of 0.05 eq., and
23.5 g of acetonitrile.
The mixture is agitated at 20.degree. C. under oxygen bubbling (.about.30
ml/mn).
After reaction for 2 to 4 hours, the ethyl .alpha.-ketobutyrate formed is
determined in the medium by HPLC (external calibration after oximation
with methoxylamine).
The results are recorded in the following Table 1:
TABLE I
______________________________________
Yield (%) *
Test Catalysts Solubility 2 hrs 4 hrs
______________________________________
1 Cu(NO.sub.3).sub.2, 3H.sub.2 O
soluble 75 >95
2 Cu(ClO.sub.4).sub.2, 6H.sub.2 O soluble 8 27
3 Cu(OAc).sub.2 4H.sub.2 O soluble 3 4
4 CuCl.sub.2, 2H.sub.2 O soluble 3 7
5 CuCl.sub.2 soluble 2 5
6 Cu(SO.sub.4).sub.2, 5H.sub.2 O slightly soluble 3 4
7 CuBr.sub.2 soluble 0 0
8 CuCl soluble 0 4
9 CuCO.sub.2, Cu(OH).sub.2 slightly soluble 0 0
10 Cu acetylacetonate slightly soluble 0 0
11 Cu ethylacetoacetate slightly soluble 0 0
12 FeCl.sub.3 soluble 65 85
13 Fe(NO.sub.3).sub.3, 9H.sub.2 O soluble 24 27
14 Co(OAc).sub.2, 4H.sub.2 O slightly soluble 1 4
15 CoCl.sub.2, 6H.sub.2 O soluble 7 13
16 Co(NO.sub.3).sub.2, 6H.sub.2 O soluble 0 0
17 Co(SO.sub.4).sub.2, 7H.sub.2 O slightly soluble 0 0
18 Mn(OAc).sub.2, H.sub.2 O slightly soluble 4 9
19 MnCl.sub.2, 4H.sub.2 O slightly soluble 2 3
20 Mn(NO.sub.3).sub.2, 6H.sub.2 O soluble 0 0
______________________________________
* determined by HPLC dosage in the reaction medium (by external
calibration after oximation with methoxylamine)
Analysis of these results clearly shows that the Cu.sup.II nitrate (test 1)
and the ferric chloride (test 12) are by far the most effective catalysts
compared with all other catalysts tested.
COMPARISON EXAMPLE 2
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a gas supply and a condenser surmounted by a gas washing bottle,
the following is weighed:
0.98 g (6 mmoles, 1 eq) of ethyl 2-ethylacetoacetate (purity .about.97%)
0.0732 g (0.3 mmole 0.05 eq.) of trihydrated copper.sup.II nitrate (purity
99% min) is added dissolved in various nitrile-type solvents
(concentration by mass of substrate: 4% with respect to the solvent).
The mixture is agitated whilst maintaining the temperature at 20.degree. C.
with a water bath under oxygen bubbling (30 ml/mn). The ethyl
.alpha.-ketobutyrate formed is determined in the reaction medium as a
function of the reaction time by HPLC (by external calibration after
oximation with methoxylamine).
The results are recorded in the following Table II:
TABLE II
__________________________________________________________________________
Test 21 22 23 24 25 26
__________________________________________________________________________
Nitriles Yield (%) * at MeCN EtCN
#STR5##
#STR6##
#STR7##
#STR8##
- 2 hrs 75 70 60 75 75 10
4 hrs >95 95 90 85 85 25
6 hrs >95 >95 >95 95 95 62
8 hrs >95 >95 >95 >95 >95 70
__________________________________________________________________________
*determined by HPLC dosage in the reaction medium (by external calibratio
after oximation with methoxylamine)
The Cu.sup.II nitrate possesses approximately the same reactivity in the
different aliphatic nitriles. It is slightly lower in the aromatic
nitrites.
COMPARISON EXAMPLE 3
The effectiveness of the catalysts Cu(NO.sub.3).sub.2, 3H.sub.2 O and
FeCI.sub.3 in various polar, apolar, protic, aprotic solvents and in
solvent mixtures, was studied.
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube, the following were introduced:
0.98 g (6 mmoles) of ethyl 2-ethylacetoacetate (purity .about.97%),
Cu(NO.sub.3).sub.2, 3H.sub.2 O or FeCI.sub.3 catalyst at the rate of 0.05
eq. and various solvents or solvent mixtures.
The mixture is agitated at 20.degree. C. under oxygen bubbling (.about.30
ml/mn).
After reaction for 2 to 4 hours, the ethyl a-ketobutyrate formed is
determined in the medium by HPLC (by external calibration after oximation
with methoxylamine).
The results are recorded in the following Table III:
TABLE III
______________________________________
Yield (%)*
Test Catalysts Solvent 2 hrs 4 hrs
______________________________________
21 Cu(NO.sub.3).sub.2, 3H.sub.2 O
acetonitrile 75 >95
27 Cu(NO.sub.3).sub.2, 3H.sub.2 O acetic acid 0 0
28 Cu(NO.sub.3).sub.2, 3H.sub.2 O ethanol 0 0
29 Cu(NO.sub.3).sub.2, 3H.sub.2 O ethyl acetate 0 0
30 Cu(NO.sub.3).sub.2, 3H.sub.2 O dimethylformamide 0 0
31 Cu(NO.sub.3).sub.2, 3H.sub.2 O toluene 0 0
32 FeCl.sub.3 acetonitrile 65 85
33 FeCl.sub.3 acetic acid 0 0
34 FeCl.sub.3 ethanol 0 0
35 FeCl.sub.3 ethyl acetate 0 0
36 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/water (75-25) 0 0
37 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/water (95-5) 19 33
38 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/toluene (30-70) 35 47
39 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/toluene (5-95) 0 0
40 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/MeCOOEt (5-95) 0 0
41 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/MeCOOEt (10-90) 15 28
42 Cu(NO.sub.3).sub.2, 3H.sub.2 O MeCN/MeCOOEt (20-80) 45 65
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*determined by HPLC dosage in the reaction medium (by external calibratio
after oximation with methoxylamine)
The copper.sup.II nitrate and the ferric chloride only show any catalytic
activity in acetonitrile. They have no activity in the other solvents, in
particular in acetic acid and ethanol.
These results also show that the reaction can be carried out in solvent
mixtures. However, the presence of acetonitrile is essential, and the
speed of the reaction increases when the proportion of acetonitrile
increases.
EXAMPLE 9
The effectiveness of the quantity of the catalyst Cu(NO.sub.3).sub.2,
3H.sub.2 O on the speed of the reaction was also studied.
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a dipping tube supplying oxygen and a condenser surmounted by a
gas washing bottle, the following were introduced:
0.98 g (6 mmoles) of ethyl 2-ethylacetoacetate (purity .about.97%),
Cu(NO.sub.3).sub.2, 3H.sub.2 O catalyst at the rate of 0.05 to 0.001 eq.,
and
23.5 g of acetonitrile.
The mixture is agitated at 20.degree. C. under oxygen bubbling (.about.30
ml/mn).
After reaction for 2 to 4 hours, the ethyl .alpha.-ketobutyrate formed is
determined in the medium by HPLC (by external calibration after oximation
with methoxylamine).
The results were recorded in the following Table IV:
TABLE IV
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Concen- Quantity Reac-
tration by of tion
mass of .beta.- catalyst temper- Yield (%)*
Test keto ester (%)
(molar %)
ature 2 hrs
4 hrs
6 hrs
8 hrs
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43 4 5 ambient
75 >95 >95 >95
44 8 5 ambient 90 >95 >95 >95
45 4 1 ambient 31 71 95 >95
46 12 1 ambient 71 81 91 >95
47 20 1 ambient 41 82 95 >95
48 30 1 ambient 46 57 66 73
49 90 2 ambient 17 21 34 48
50 20 0.1 50.degree. C. / / >95 >95
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*determined by HPLC dosage in the reaction medium (by external
calibration, after oximation with methoxylamine).
The reaction is enhanced by increasing the quantity of metallic salt. A
higher temperature allows this quantity to be reduced. The quantity of
nitrile is equally significant. A concentration of 20 to 25% of substrate
in the mixture is preferred.
EXAMPLE 10
In a 100 ml three-necked flask equipped with a thermometer, a magnetic
stirrer, a gas supply and a condenser surmounted by a gas washing bottle,
the following are introduced:
0.98 g (6 mmoles, 1 eq.) of ethyl 2-ethylacetoacetate (purity .about.97%)
0.0732 g (0.3 mmole 0.05 eq.) of trihydrated copper.sup..parallel. nitrate
(purity 99% min), and
23.5 g of acetonitrile.
The mixture is agitated whilst maintaining the temperature at 20.degree. C.
with a water bath under air bubbling (85 ml/mn). 0.78 g of ethyl
.alpha.-ketobutyrate is determined in the reaction medium after 4 hours by
HPLC (by external calibration after oximation with methyloxylamine) (yield
>95%).
EXAMPLE 11
In a 2 l glass autoclave equipped with mechanical agitation, a gas supply,
a thermometer and a double jacket oil circulation heater, the following
are introduced:
135 g (0.85 mol, 1 eq.) of ethyl 2-ethylacetoacetate
2 g (0.0085 mol, 0.01 eq.) of trihydrated copper.sup.II nitrate,
500 g of acetonitrile.
The mixture is agitated whilst maintaining the temperature constantly below
40.degree. C. and the reactor is charged with oxygen under a pressure of 5
bars. As soon as the pressure drops below 2 bars, the oxygen is recharged
(5 bars), and so on until the oxygen consumption is negligible
(approximately 6 hours).
The medium is then distilled under reduced pressure and 77 g of ethyl
.alpha.-ketobutyrate is obtained, i.e. a yield of approximately 70% (by
direct GC).
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